DK160762B - ANALOGY PROCEDURE FOR PREPARING 2-PHENYL OR 2-PYRIDYL-PYRAZOLOOE4,3-CAAQUINOLIN-3 (1 AND 5H) -ON-COMPOUNDS OR THE 3-HYDROXYTA AUTOMERS OR SALTS THEREOF - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A compound of the general formulae I and II see diagramm : EP0022078,P19,F1 and see diagramm : EP0022078,P19,F2 wherein R3 is hydrogen or not more than 3 identical or different members selected from C1 -C7-alkyl, C1 -C7 -alkoxy, C1 -C7 -alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-C1 -C7 -alkylamino, cyano, carbamoyl and carboxyl ; R is phenyl or phenyl substituted by not more than 3 of the radicals as defined for R3 , pyridyl, C1 -C7 -alkylpyridyl, or halopyridyl ; R1 is hydrogen, C1 -C7 -alkyl or (hydroxy, di-C1 -C7 -alkyl-mino or R3 -phenyl)-C1 -C7 -alkyl, wherein the hydroxy or amino group is separated from the ring nitrogen atom by at least 2 carbon atoms, and R2 is hydrogen or C1 -C7 -alkyl ; their 3-hydroxy-tautomers ; C1 -C7 -alkanoyl, carbamoyl, mono- or di-C1 -C7 alkylcarbomoyl derivatives of said (hydroxy or amino)-(phenyl or phenylene) compounds ; or salts thereof. For the Contracting State AT 1. A process for the preparation of a 2-aryl-pyrazolo [4,3-c] quinolin-3-(1 or 5H)-one of the general formulae I and II see diagramm : EP0022078,P21,F1 and see diagramm : EP0022078,P21,F2 wherein R3 is hydrogen or not more than 3 identical or different members selected from C1 -C7 -alkyl, C1 -C7 -alkoxy, C1 -C7 -alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-C1 -C7 -alkylamino, cyano, carbamoyl and carboxy ; R is phenyl or phenyl substituted by not more than 3 of the radicals as defined for R3 , pyridyl, C1 -C7 -alkylpyridyl, or halopyridyl ; R1 is hydrogen, C1 -C7 -alkyl or (hydroxy, di-C1 -C7 -alkylamino or R3 -phenyl)-C1 -C7 -alkyl, wherein the hydroxy or amino group is separated from the ring nitrogen atom by at least 2 carbon atoms, and R2 is hydrogen or C1 -C7 -alkyl ; their 3-hydroxy-tautomers ; C1 -C7 -alkanoyl, carbamoyl, mono- or di-C1 -C7 -alkylcarbamoyl derivatives of said (hydroxy or amino)-(phenyl or phenylene) compounds ; or a salts thereof, which comprises a) cyclising a compound of the formula IV see diagramm : EP0022078,P21,F3 wherein X is -NH-NH-R and Y is hydroxy or C1 -C7 -alkoxy ; or X is halogen and Y is see diagramm : EP0022078,P21,F4 ; or X is C1 -C7 -alkoxyamino or azido, and Y is NH-R, and, if desired, reacting a resulting compound, or an alkali metal salt thereof, with a reactive ester of the alcohol R1 -OH, or b) condensing a compound of the formula V see diagramm : EP0022078,P21,F5 wherein W and R1 are both hydrogen, Z is see diagramm : EP0022078,P21,F6 and R1 ' is C1 -C7 -alkyl ; or W is see diagramm : EP0022078,P22,F7 and Z is hydrogen ; or W is see diagramm : EP0022078,P22,F8 and Z is R2 -CO, or see diagramm : EP0022078,P22,F9 together is isocyano ; and, if desired, converting a resulting compound into another compound of the invention, and/or, if desired, converting a resulting compound into a salt thereof, or a resulting salt into the corresponding free compound or into another salt, and/or, if desired, separating a mixture of isomers obtained into the individual isomers.

Description

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in

The present invention relates to an analogous process for the preparation of novel 2-phenyl or 2-pyridyl-pyrazolo [4,3-c] quinoline-3 (1 and 5H) -one compounds 5 of the general formulas

D Ri N-N R M_M D

btf · - bbb N ^^ R2 i

R 1 (I) (II) wherein R 3 represents hydrogen, lower alkoxy, halogen or trifluoromethyl, R means unsubstituted or having at most 2 identical or different substituents selected from lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-lower alkylamino, cyano, carbamoyl and lower alkylcarbamoylamino substituted phenyl, pyridyl, lower alkylpyridyl or halogenpyridyl, R ^ means hydrogen, lower alkyl or di-lower alkylamino lower alkyl, and R2 represents hydrogen or lower alkyl, wherein the "lower" groups contain 1 -4 carbon atoms, the 3-hydroxytautomers, or their salts. 1

Monatsh. 57, 52 (1931) disclosed 2-unsubstituted 4-phenyl-pyrazolo [4,3-c] quinolin-3-ones or their 3-hydroxytautomers. 2-Phenyl-pyrazolo [3,4-c] isoquinolin-3-ones (or 3-ols) are described in J. Chem.

Soc. 1959, 599, and in the specification for European Patent Application No. 5745, 3-phenyl-pyrazolo [4,3-c] isoquinolin-5-one with anti-inflammatory, CNS depressant and anti-anxiety effects is described. Finally, U.S. Patent No. 3,890,324 discloses 1H-pyrazolo [4,3-c] quinol-4- [5H] one-3-carboxylic acids with anti-inflammatory action.

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It has now surprisingly been found that compounds of formulas I and II are valuable psychoactive compounds.

The phenyl group is unsubstituted or substituted with one substituent R 3 selected from lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or n- or i-butoxy, halogen, e.g. fluorine, chlorine or bromine, or trifluoromethyl.

The phenyl or pyridyl group R at the 2-position is preferably an ortho-unsubstituted phenyl group which, as the above-defined phenyl group, is unsubstituted or contains at most two substituents, but also 3-, 4- or 2-pyridyl or a mentioned alkylated or halogenated pyridyl group, preferably (4-methyl or 5-chloro) -2-pyridyl. Of the substituents listed above, starting with trifluoromethyl, only one such substituent is preferably present.

The group R 1, in either the 1- or preferably 5-position, is preferably hydrogen, but may also be a low-alkyl group or a di-lower alkylamino-lower alkyl group wherein the adjacent heteroatoms are separated by at least 2 carbon atoms. Such groups are 2- (dimethylamino or diethylamino) -ethyl or 2- or 3- (dimethylamino) propyl.

The group R2 in the 4-position is hydrogen or a lower alkyl group, especially methyl.

Because of said 1- or 5-substituent R 1, the compounds of the invention are properly designated as 3-ones or as 3-oxo derivatives. However, if R 1 is hydrogen, the compounds, depending on the environment and substitution, may form a smaller amount of tautomeric 3-hydroxy compounds. Usual- 3

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however, they are weak bases or acids, which form salts either with strong acids or bases. Only the below (hydroxy or amino) phenyl compounds form acyl derivatives. The acyl derivatives are low alkanoyl, carbamoyl, mono or dilavalkylcarbamoyl derivatives of the aforementioned (hydroxy or amino) phenyl compounds or (hydroxy or amino) phenylene compounds. Such derivatives are e.g. acetyl, propionyl, pivaloyl, (methyl or ethyl) carbamoyl derivatives. Salts are preferably alkali metal salts, e.g. sodium or potassium salts of 1- or 5-unsubstituted compounds (R1 = H) and / or of carboxy (phenyl or phenylene) compounds or acid addition salts of all of the said 15 compounds with acids, especially with the acids listed below.

The term "low" as used hereinbefore and hereinafter shall be understood to mean such organic groups or compounds containing not more than 4, especially 20 1 or 2, carbon atoms.

The compounds of the invention have valuable pharmacological properties, namely psychoactive effects, primarily anti-depressant or anxiolytic effect. These effects can be demonstrated using in vitro or in vivo test methods, preferably using mammals, e.g. mice, rats or monkeys, as experimental animals. Said compounds may be administered to the test animals enterally or parenterally, preferably orally, or subcutaneously, intravenously or intraperitoneally, e.g. by plug capsules or in the form of starchy suspensions or aqueous solutions or suspensions. The dosage used may be in a range of approx. 0.01 to approx. 100 mg / kg / day, preferably approx. 0.05 to approx. 5 mg / kg / day, especially from 0.1 to 0.5 mg / kg / day.

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The aforementioned anti-depressant properties can be detected in mice by the "Behavioral Despair" test (Arch. Int. Pharmacodyn. Ther. 229 (2), 327-336, October 1977). In this experiment, the test animal is forced to swim in a narrow cylinder from which it cannot escape, thereby triggering a depressive state. After a short period of lively activity, the mouse occupies a characteristic motionless posture that can be easily detected.

The onset of this immobility is diminished by the compounds of this invention in a similar manner as with other tricyclic antidepressants, monoamine oxidase inhibitors, atypical antidepressants or by electroconvulsive shocks.

The anxiolytic effects are routinely ascertained using the classic rat metrazole antagonism test or using the Cook-Davidson Conflict method using male Wistar rats. These rats are maintained using a diet of 80% of their normal body weight, though there is unlimited access to water. They are trained to press a switch in a conditioning chamber. The chamber also contains a drop pipette for liquid, a light source, a speaker and a grille bottom. Both the switch and the grille are connected to an electric shock source.

25 The chamber is housed in a muffled room in which during the course of the experiment a white noise source shields the external hearing impressions. Each trial period of 47 minutes consists of two alternating programs. The first is a Variable Interval (V1) program of 30 se-30 customers, repeated within 5 minutes. In this program, a ration of sweetened condensed milk was given to the rats 30 seconds after the first activation. The decrease in activation of the active substance by the active substance is considered as evidence of the neurological deficit.

35 Immediately after the VI program, a 1000 Hz tone and a light signal indicating the beginning of 5

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the second so-called Fixed Ratio (FR) program, which lasts for 2 minutes. During this time interval, immediately after the tenth pressure on the switch, at the same time as the milk ration, a 5 electric shock occurs in the feet, resulting in a conflict situation. Said shock has an intensity of between 2.0 and 3.6 mA. It varies for each test animal, so that during the entire treatment period it is set to approx.

25 to 100 contact pressures during this program. The increase of this active substance induced by the active substance during the FR program is a reference to the anxiolytic effect shown by the compounds of the present invention.

The anxiolytic effect of the compounds of the invention can also be assessed using the "Diazepam Receptor Binding" test in vitro, e.g. as described in Nature 266, 732 (1977) or in Proc. Night. Acad. Sci. USA 74, 3805 (1985). The diazepam binds specifically and with greater affinity to crude brain synaptosomal membrane preparations in rats.

This binding is inhibited by other anxiolytic compounds, e.g. of pharmacologically active benzodiazepines. Using diazepam labeled with tritium, the interaction between other active substances and said receptor can be readily assessed as follows: membranes from 25 rat brains are incubated at 0-5 ° C with diazepam labeled with tritium and at different concentrations. of the test compound in a physiological medium at a pH of 7.5. The membranes containing the receptors with different amounts of the tritium-labeled diazepam are filtered on fiberglass filters. These are then shaken in a liquid scintillation counter. The concentration of the subject compounds required for 50% inhibition of the specific binding of 2 nM with tritium labeled diazepam, i.e. The IC-50 (Inhibitory Concentration) value 35 can be calculated graphically. This concentration goes down to an area of approx. 0.6 nM. This concentration is, on the order of magnitude, lower than the concentration of 6

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diazepam (5 nM) and nearly four potencies lower than the value for chlorine diazepoxide (400 nM).

The table below lists ICsg values for some of the 5 compounds. The ICscr values are determined as described above.

Table.

Compound according to IC value Compound according to IC value Q nancmol ex no nanerol 1 0.7 24/2. 13.0 4 600 24/3 1.0 5 700 24/4 0.5 6 / b 600 24/6 20 8 20 24/8 100 9 / a 10 24/11 1.5 10 0.4 24/14 0.9 11 / a 0.75 24/17 0.75 11 / b 0.5 24/19 4.0 12 0.6 24/28 0.27 13 1.0 24/31 1.1 14 9, 0 24/37 0.17 15 2.0 24/40 0.3 16 1.0 24/46 20 17 1.5 24/48 10 24/1 0.7 24/50 10 25 / b 500 2 5 / c 6 7

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Accordingly, the compounds of the present invention are valuable in the treatment of mental depression, preferably in the control of anxiety states similar to those treated with diazepam. In contrast to diazepam, the compounds of this invention at doses at which the anxiety-relieving effect already occurs have no tendency to trigger a neurological deficit. In addition, the compounds of this invention can be used as intermediates for the preparation of other valuable, especially pharmacologically effective, compositions.

The compounds of the formula for ref. Xa '• f «· · r" - + - Il II (III), «· ·

VY

H

wherein R "means hydrogen, alkoxy of 4 carbon atoms, fluorine, chlorine, bromine or trifluoromethyl, R 'means hydrogen, o- or m-fluorine or p-fluorine when R" means chlorine, or the salts, especially the pharmaceutically useful alkali metals - or acid addition salts thereof, are preferred because of their predominantly antidepressant effect.

In particular, the compounds of formula III in which R "has the meanings given in the preceding paragraph must be emphasized, R 'is alkyl or alkoxy with every 4 carbon atoms, hydroxy, chloro, bromo, trifluoromethyl, nitro, amino, monoalkylamino or alkylcarbamoylamino having not more than 4 25, or means p-fluoro when R "is different from chlorine, or the salts, especially pharmaceutically useful alkali metal or acid addition salts thereof, because of their predominantly anxiolytic effect.

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The compounds of formula III should be highlighted in which R "is hydrogen or 8- (methyl, methoxy, fluorine or chlorine) and R 1 is hydrogen or means 4-fluoro when 5 R" is 8-chloro, or the salts, especially the pharmaceutically useful alkali metal or acid addition salts thereof, because of their predominantly antidepressant effect.

In particular, the compounds of formula III should be highlighted wherein R "means hydrogen or 8- (methoxy, fluorine or chlorine), 10 and R 'means hydrogen or 4-fluoro when R" means 8-chloro, or the salts, especially those pharmaceutically useful alkali metal or acid addition salts thereof, because of their predominantly anxiolytic effect.

Also preferred are compounds of the general formula III wherein R 1 is hydrogen and R "is hydrogen, 8- (methoxy, fluoro or chloro), or R 'is 4-fluoro and R" is 8-chloro, or the salts , especially the sodium salts, hydrochlorides or methanesulfonates thereof, because of their predominantly antidepressant effect.

Particularly preferred are the compounds of formula III wherein R 'is 4- (methyl, chloro or amino) and R' is hydrogen, or the salts, especially the sodium salts, hydrochlorides or mesylates thereof, because of their predominantly anxiolytic effect.

The process of the invention is characterized in that compounds of formula are learned. i ^ \ / r, —f- i rCOT <IV> ·

VV

9

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wherein X is -NH-NH-R, where R and R3 have the meanings given above and Y is hydroxy or lower alkoxy,

5b) cyclically terminates compounds of formula IV wherein X

means halogen and Y means I

H 2 N-R,

wherein R and R3 have the above meanings, or cc) terminates compounds of formula IV wherein X

10 is lower alkoxyamino and Y is -NH-R and R and R3 have the meanings given above, 2a) condenses compounds of the formula

VT "TR

(/ Y% (Va)% \, I! Ϊ́ II C-R0 w

H

wherein R 1 represents lower alkyl R, R 2 and R 3 have the above meanings, 2b) condenses compounds of the formula

fairy

% \ / V ° • · i II 1% / \ C0R_ • Vh 2 i

H

wherein R, R2 and R3 have the above meanings, 2c) condenses compounds of the formula

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10

v JCT

3> y h VV »*

H

wherein R, R 2 and R 3 have the above meanings, and (a) when a compound in which R 1 is at 1 position 5 is different from hydrogen, a resulting compound wherein R 1 is hydrogen reactes with a reactive ester of an alcohol R 1'-OH wherein R 2 is as defined above for R 2 other than hydrogen, b) when a compound is desired wherein R 1 at 5 position 10 is different from hydrogen, an alkali metal salt of an a compound wherein R 1 is hydrogen, with a reactive ester of an alcohol R 1'-OH, wherein r 1 is the one given above for R 2 other than hydrogen, (c) when a compound in which the phenyl group R is substituted is desired with hydroxy, a lower alkoxy substituent on the phenyl group R, d) hydrolyzes when a compound in which the phenyl group R is substituted with amino reduces a nitro substituent on the phenyl group R, e) when a compound in which the phenyl group R is substituted with mono- or di-low alkylamino, alkylates the amino substituent on the phenyl group R, f) when a compound in which the phenyl group R is substituted with lower alkylcarbamoylamino, acylates an

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or g) when a compound in which the phenyl group R is 5 is substituted with carbamoyl converts a cyano substituent on the phenyl group R to carbamoyl and then, if desired, h) converts a resultant compound to its salt or an resulting salt to the free compound or to another salt, and / or 10 i) if desired, a resulting isomer mixture separates into the individual isomers.

In process 1), the cyclization of said acids or amides of formula IV can be carried out by heating to temperatures between ca. 80 and 180 ° C, preferably in the presence of inert solvents, e.g. aliphatic or aromatic hydrocarbons and / or ethers, e.g. toluene, xylenes, biphenyls and / or diphenyl ether, distilling off the water or alkanol formed. The indicated hydrazides of formula 20 IV can be cyclized in an analogous manner, but preferably under basic conditions, e.g. in the presence of aqueous alkali metal hydroxide solutions, to neutralize the formed hydrogen halide acids. The cyclization of the said amides of formula IV may be effected by heating 25 to temperatures between ca. 120 and approx. 300 ° C, preferably between 200 and 250 ° C, especially also in the presence of one of said inert solvents.

Some of the starting compounds of formula IV are novel compounds. However, they can easily be made out 12

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from correspondingly known compounds wherein X represents hydroxy by condensation with corresponding aryl hydrazines. Such methods are, for example, illustrated in the Examples or described in J.Med.Chem. 12, 1096 (1969) or C.R. Acad. Sc. Paris, T. 280, C, 1385 (1975). Said hydrazides can be prepared by condensation of 4-chloroquinoline-3-carboxylic acid chlorides and β-acylated aryl hydrazines, e.g. trifluoroacetates which hydrolyze under the cyclization conditions. The said amides are preferably prepared by condensation of 4-haloquinoline-3-carboxylic acid halides with R-amines and then with O-low alkyl hydroxylamines or alkali metal azides.

In process 2) the condensation of the starting compounds of formula Va is preferably carried out with strong aprotic condensing agents, e.g. polyphosphoric phorsyrelavalkylestere. When starting compounds of formula Vb are used, the water formed by the cyclization reaction is preferably azeotropically removed. The reaction 20 is preferably carried out in the above hydrocarbons and / or ethers, if desired, in the presence of conventional molecular sieves and / or in the presence of catalytic amounts of an acid, e.g. hydrochloric acid.

Finally, compounds of formula Vc may be cyclized under neutral conditions, optionally in the presence of dehydrating agents such as e.g. thionyl halides, phosphorus oxyhalides or polyphosphoric acid lower alkyl esters.

The starting compounds of formula V are also novel compounds. They can be prepared in known manner, e.g. by condensation of 1-aryl-pyrazolidine-3,5-dione with ortho-formic acid ethyl ester and an aniline. Said second starting compound of formula V can be prepared analogously to the process of Izv. Akad. Nauk. Latv. SSR.

35 1965, 587, however, using analogous compounds 13

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with an o-nitro group which is then reduced with catalytically activated hydrogen. The latter group of starting compounds of formula V can be prepared in a similar manner from said conventional 1R-3- (o-nitrophenyl) -5-pyrazolones by reduction, N-acylation and, if desired, dehydration to said isonitriles with phosgene. or dimethylformamide / thionyl halide mixtures.

The compounds produced can be converted into each other in a manner known per se. Thus, for example, compounds wherein hydrogen is substituted at the 1-position with a reactive ester of R 2 -OH. These esters are derived from e.g. hydrogen halide acids, aliphatic or aromatic sulfonic acids and are e.g. R 1 (halogenides, sulfates, aliphatic or aromatic sulfonates) such as methyl iodide, dimethyl sulfate, benzyl chloride or methanesulfonic acid or toluene sulfonic acid methyl ester. In this way, 1-substituted compounds of formula I. are obtained. Compounds of formula II can be prepared in a similar manner from corresponding alkali metal salts, e.g. in which R 1 represents sodium or potassium, the substitution taking place at the 5-position. Furthermore, prepared lower alkoxy compounds can be hydrolyzed to the corresponding phenols with strong hydrogen halide acids, e.g. hydrobromic acid. Nitro compounds produced can be reduced to the corresponding amines with catalytically activated or nascent hydrogen, e.g. hydrogen in the presence of noble metal catalysts such as nickel, palladium or platinum catalysts, or with hydrogen formed by the action of reactive metals on alcohols or acids, e.g. zinc and hydrogen halide acids. Said amines may be alkylated in the same manner as described for the compounds having R 1 = H or by reductive alkylation or e.g. is alkylated with the corresponding reactive acid derivatives, e.g. anhydrides, halides or isocyanates. Nitriles produced can be transferred into the corresponding amides of known per se 14

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way, e.g. by treatment with aqueous alkali metal hydroxide solutions, e.g. aqueous sodium hydroxide solution, ethanol and hydrogen peroxide, or by hydrolysis are converted to the corresponding acids, e.g. with aqueous alkali metal hydroxide solution such as aqueous sodium hydroxide solution.

Finally, a compound prepared can be transferred into an alkali metal salt, preferably using alkali metal hydrides, hydroxides or low alkoxides, or in an acid addition salt (especially in the case of amino-substituted compounds), preferably using inorganic or organic acids. , which leads to therapeutically useful salts. Such acids are, for example, strong inorganic acids, such as hydrogen halide acids, e.g. hydrochloric or hydrobromic, sulfuric, phosphoric, nitric or perchloric, or aliphatic or aromatic carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxy acid benzoic acid , nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylene sulfonic acid, halobenzene sulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulphanilic acid, cyclohexylsulfamic acid or ascorbic acid. These or other salts, e.g. The picrates can also be used to purify the amino bases. The bases are transferred into the salts which are isolated and the free compounds are released from the salts. Acid addition salts of compounds which do not have basic substituents, e.g. which lack amino groups, usually hydrolyzes in approximately neutral aqueous media.

The reactions described above are carried out in a manner known per se, in the presence or absence of diluents, preferably in those which are inert.

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to the reactants and dissolving them, catalysts, condensing or neutralizing agents, and / or in an inert atmosphere, under cooling, at room temperature or at elevated temperature, preferably at the boiling point of the solvent used, at normal pressure or at elevated pressure.

Produced isomer blends can be divided into individual isomers in a manner known per se, e.g. by fractionated distillation, crystallization and / or chromatography.

Preferably, in the process of the present invention, such starting compounds are used which lead to those compounds which have previously been referred to as particularly valuable, especially to compounds of formula III.

The pharmacologically useful compounds can be used for the preparation of pharmaceutical compositions containing an effective amount of the active substance together with or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active substance are used together with diluents, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants such as e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. The tablets also contain binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. starch, agar, alginic acid or a salt thereof, enzymes for the binder and / or shower mixtures or adsorbents, dyes, flavors and sweeteners.

Preferably, injectable compositions are isotonic aqueous 16

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solutions or suspensions, and suppositories are primarily fat emulsions or suspensions. The pharmacological compositions may be sterilized and / or contain excipients, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solubility enhancers, salts for regulating the osmotic pressure and / or buffers. The pharmaceutical compositions, which if desired may contain 10 other pharmacologically valuable substances, are prepared in a manner known per se, e.g. using conventional mixing, granulating or coating methods, and containing from ca. 0.1 to approx. 75, especially from ca. 1 to approx.

50%, of the active substance.

The following examples serve to illustrate the invention. The parts listed are by weight, and unless otherwise stated, the evaporation of solvents is done under reduced pressure, e.g. between approx. 0.1 and 15 mm Hg.

The compounds listed in the following examples having a high melting point are characterized by their IR or NMR spectra.

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Example 1.

A mixture of 1681 g of 4-chloro-quinoline-3-carboxylic acid ethyl ester, 1017 g of p-chlorophenyl-hydrazine and 25,000 ml of xylene is heated under stirring in a nitrogen atmosphere for 24 hours to 105 ° C. The resulting suspension is cooled to 20 ° C and 14,000 ml of 2N aqueous sodium hydroxide solution is added, then stirred for 15 minutes and diluted with 30,000 ml of water. Stirring is continued for 1 hour, then the aqueous phase is isolated and washed with five times 8000 ml of diethyl ether, then filtered and the filtrate is treated with a solution of 1600 g of ammonium chloride in 8000 ml of water while stirring in a nitrogen atmosphere. The resulting suspension is stirred overnight at room temperature, filtered and the residue is washed with five times 12,000 ml of warm water. The residue is dried at 5 mm Hg and 90 ° C, and 1665 g thereof is dissolved in 8400 ml of dimethylformamide at 130 ° C. The solution is filtered and then stirred to cool to room temperature. The resulting suspension is filtered, washed with twice twice 500 ml of cold dimethylformamide and four times 1000 ml diethyl ether, then the residue is dried at 0.1 mm Hg and 100 ° C. In this way 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one of formula N-N - <3

H

25 which melts during decomposition at 324-327 ° C.

The starting material is prepared as follows (according to a generally applicable procedure): To 1272 g of aniline is added over 20 minutes and with stirring 2953 g of ethoxy-methylene-malonic acid diethyl ester and stirring is continued 18

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for 135 minutes at 90-92 ° C. The ethanol formed is distilled off for four hours at 10 mm Hg and 80 ° C. As the residue, an oil is obtained which crystallizes on plates. The crystals are pulverized and dried at 5 mm Hg and room temperature. In this way, phenylaminomethylene malonic acid diethyl ester is prepared which melts at 45-46 ° C.

1085 g of the compound prepared above is added over 45 minutes to 10,850 ml of a eutectic mixture of diphenyl ether and biphenyl (73.5: 26.5 parts by weight) under ni-10 trogen and with stirring at 215-220 ° C. Upon completion of the addition, the temperature is raised to 238 ° C and the resulting mixture of ethanol and diphenyl ether is captured over a period of four hours in a separator (about 390 ml). The reaction mixture is left stirring to cool to room temperature. The resulting suspension is filtered, the residue washed with twice 500 ml of diethyl ether and dried at 0.1 mm Hg and 85 ° C. In this way, 4-hydroxyquinoline-3-carboxylic acid ethyl ester is prepared, which melts at 276-280 ° C.

1630 g of the above compound are added over 20 minutes with stirring in a nitrogen atmosphere to 2463 ml of phosphorus oxychloride. The mixture is stirred for 15 minutes at 70 ° C and for 2 hours at 95 ° C, after which the liquid is distilled off at 11 mm Hg and 60 ° C. The residue is dissolved in 8000 ml of methylene chloride, the solution is cooled to 0 ° C and 25 g of crushed ice are added. The mixture is stirred, treated with 3000 ml of 50% aqueous sodium hydroxide solution at a temperature below 15 ° C and when the pH reaches 12, the organic phase is isolated. This is washed twice with 2000 ml of water, with 2000 ml of saturated aqueous sodium chloride solution, after which it is dried and evaporated. The oil obtained as the residue is recommended for crystallization on plates. The crystals are pulverized and dried at 0.1 mm Hg at room temperature. In this way, 4-chloroquinoline-3-carboxylic acid ethyl ester is prepared, which melts at 44-46 ° C.

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To a solution of 1445 g of p-chloroaniline in 3375 ml of 38% hydrochloric acid and 5650 ml of water is added at -5 to -8 ° C over 1 hour with stirring in a nitrogen atmosphere a solution of 793 g of sodium nitrite in 3300 ml of water. After 15 minutes, 7617 g of stannous chloride in 9000 ml of 38% hydrochloric acid are added over 30 minutes and at a temperature below 25 ° C. The resulting suspension is stirred for 1 hour in an ice bath and filtered. The residue is suspended in 30,000 ml of water and added with stirring in a nitrogen atmosphere 5000 g of solid sodium hydroxide over 1 hour at 0-25 ° C. The mixture is extracted with twice 8000 ml of diethyl ether, the combined extracts are washed with twice 4000 ml of water and again with saturated aqueous sodium chloride solution, then dried, filtered and evaporated. The residue is dried at 5 mm Hg and room temperature. In this way, the p-chlorophenyl hydrazine is prepared, which melts at 82-87 ° C.

Example 2.

A mixture of 1 g of 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one and 3.38 ml of 1 N aqueous sodium hydroxide solution is stirred in a nitrogen atmosphere overnight at room temperature.

The resulting solution is filtered, evaporated and the residue is dried under reduced pressure. In this way, the corresponding sodium salt is prepared, which melts at 280-284 ° C.

Example 3

A mixture of 1 g of 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-2 (5H) -one, 20 ml of trifluoroacetic acid and 0.325 g of methanesulfonic acid is stirred for 1 hour at room temperature and evaporated. The residue is triturated with diethyl ether and filtered off. In this way, the corresponding methanesulfonate is prepared which melts at 250-255 ° C.

Example 4

A mixture of 3 g of 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinoline-3 (5H) -one and 100 ml of dimethyl sulfate is stirred and evaporated at 20

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110-130 ° C for two hours. The residue is dissolved in 1 N aqueous sodium hydroxide solution / extracted with methylene chloride and the extract is evaporated. The residue is recrystallized from diethyl ether. In this way, 1-methyl-2- (p-5-chlorophenyl) -pyrazolo [4,3-c] quinolin-3-one is formed, which melts at 158-161 ° C.

Example 5

A mixture of 5 g of 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, 0.81 g of 50% sodium hydride in mineral oil and 100 ml of anhydrous tetrahydrofuran are boiled for 2 minutes. hours under reflux. The mixture is cooled to room temperature, 3 g of methyl iodide is added with stirring, and after an hour, an additional 1 g of methyl iodide is stirred. The mixture is stirred overnight at room temperature, then filtered and the residue recrystallized from a mixture of tetrahydrofuran and heptane.

In this way, 5-methyl-2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3-one is prepared, which melts at 322-323 ° C.

Example 6

A solution of 10 g of 2- (p-chlorophenyl) -pyrazolo [3,4-c] quinoline-3 (5H) -one, 1.8 g of 50% sodium hydride in mineral oil and 250 ml of 1.2 -dimethoxyethane is stirred to solution at 100 ° C. The mixture is cooled to room temperature and 15 g of 3-dimethylamino-propyl chloride is added in 10 ml of 1,2-dimethoxyethane. The mixture is dried at 150 ° C overnight, then cooled and the above solution decanted, after which the residue is treated with said solution. In this way, 5- (3-dimethylaminopropyl) -2- (p-chlorophenyl) pyrazolo [4,3-c] quinolin-3-one is prepared which melts at 189-191 ° C.

Analogously, 5- (2-dimethylaminoethyl) -2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3-one is prepared which melts at 184-186 ° C.

Example 7

A mixture of 2 g of 2- (p-chlorophenyl) pyrazolo [4,3-c] quinoline-21

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3 (5H) -one, 0.33 g of 50% sodium hydride in mineral oil and 50 ml of 1,2-dimethoxyethane are stirred at 100 ° C to form a solution. The solution is cooled to room temperature, then 3.9 g of o-fluorobenzyl chloride is added in 2 ml of 1,2-dimethoxyethane and the mixture is refluxed for 4 hours.

The mixture is then cooled to room temperature, then filtered, the residue washed with diethyl ether, slurried in 10 ml of 1 N aqueous sodium hydroxide solution, filtered again, washed with water and dried. In this way, 5- (o-fluorobenzyl) -2- (p-chlorophenyl) pyrazolo [3,4-c] quinolin-3-one is prepared which melts at 338-339 ° C.

Example 8.

A mixture of 3.5 g of 4- (2,4-dichlorophenyl-hydrazino) -quinoline-3-carboxylic acid ethyl ester and 40 ml of eutectic diphenyl ether-biphenyl is heated for 4 hours to 175 ° C, then the mixture is cooled to room temperature and diluted with diethyl ether. The resulting suspension is filtered, the residue washed with diethyl ether and dissolved in 1N aqueous sodium hydroxide solution. The solution is washed with diethyl ether and adjusted to pH 8.5 with ammonium chloride and the resulting precipitate is filtered off. The precipitate is washed with water, methanol and diethyl ether in that order. In this way, 2- (2,4-dichlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, whose IR spectrum has 25 bands at 890, 867, 845, 832, 816, 796, is prepared. , 775, 767, 756, 730 -1 and 701 cm

The starting material is prepared as follows: A mixture of 2.8 g of 4-chloroquinoline-3-carboxylic acid ethyl ester, 2.1 g of 2,4-dichlorophenyl-hydrazine and 40 ml of eutectic diphenyl ether-biphenyl is heated under stirring overnight to 80 ° C. 90 ° C. The mixture is cooled to room temperature, diluted with ether and the precipitate is isolated. The precipitate is taken up in 1 N aqueous sodium hydroxide solution, the solution is extracted with diethyl ether, the extract is washed with water, dried, filtered and concentrated and the precipitate is isolated. On this 22

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For example, 4- (2,4-dichlorophenylhydrazino) -quinoline-3-carboxylic acid ethyl ester is prepared which melts at 151-153 ° C.

Example 9

A mixture of 3.6 g of 4-chloro-2-methyl-quinoline-3-carboxylic acid ethyl ester, 1.8 g of phenylhydrazine and 40 ml of xylene is refluxed for 4 hours, after which the mixture is cooled to room temperature, diluted with diethyl ether and filtered. The residue is dissolved in 50 ml of 2 N aqueous sodium hydroxide solution, washed with diethyl ether and adjusted to pH 8.5 with ammonium chloride at 10 pH. The resulting precipitate is isolated and washed with hot water, methanol and diethyl ether in that order. In this way, 4-methyl-2-phenyl-pyrazolo [4,3-c] quinolin-3 (5H) -one, whose IR spectrum has bands at 874, 867, 858, 850, 822, 780, 765, is prepared. 756, 750, 15 740 and 722 cm -1.

Analogously, 4-methyl-2- (p-chlorophenyl) -pyr-azolo [4,3-c] quinoline-3- (5H) -one is prepared, m.p. 349-350 ° C.

Example 10.

A mixture of 2.7 g of 4-chloro-6-methoxy-quinoline-3-carboxylic acid ethyl ester, 1.4 g of p-fluorophenylhydrazine and 20 ml of eutectic diphenyl ether biphenyl is heated to 160-165 ° C for 4 hours, then the mixture is cooled to room temperature and diluted with diethyl ether. The precipitated crystalline product is isolated, washed thoroughly with diethyl ether and dried. In this way, 2- (p-fluorophenyl) -8-methoxy-pyrazolo [4,3-c] quinoline-3 (5H) -one hydrochloride is prepared which melts at 322-324 ° C.

Example 11.

A mixture of 4 g of 4-chloroquinoline-3-carboxylic acid ethyl ester, 2.04 g of 2-hydrazino-pyridine and 50 ml of eutectic diphenyl ether-biphenyl is stirred in a nitrogen atmosphere for 3 hours at 110-130 ° C. The mixture is cooled to room temperature 23

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in turn, diluted with diethyl ether, filtered, the solid washed with diethyl ether and dissolved in 100 ml of aqueous sodium hydroxide solution. The solution is washed with diethyl ether and adjusted to pH 8.5 with ammonium chloride.

The resulting precipitate is isolated and washed with water, methanol and diethyl ether in that order. In this way, 2- (2-pyridyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, whose IR spectrum has bands at 887, 865, 853, 788, 780, 765, 756, is prepared. 737 and 726 cm 10 In an analogous manner, 8-fluoro-2- (2-pyridyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, whose IR spectrum has bands at 895, 868, is prepared. , 826, 792, 776, 758 and 725 cm-1.

The starting material for the above compound is prepared as follows: A mixture of 28.9 g of 6-fluoro-4-hydroxy-quinoline-3-carboxylic acid ethyl ester [J.A.C.S. 69, 371 (1947)] and 240 ml of phosphorus oxychloride are boiled for 3 hours in a refluxing nitrogen atmosphere. Then, cool to room temperature, evaporate the solution and treat the residue with ice water and chloroform. The organic layer is dried and evaporated.

The residue is taken up in aqueous sodium bicarbonate solution and diethyl ether and the ether layer is dried and evaporated. In this way, 4-chloro-6-fluoro-quinoline-3-carboxylic acid ethyl ester is prepared, which melts at 55-57 ° C.

Example 12.

A mixture of 3 g of 2- (p-methoxyphenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one and 260 ml of 48% hydrogen bromic acid is refluxed for 1 hour, then concentrated to ca. .

50 ml. The concentrate is cooled to room temperature, the precipitate is isolated, washed with methanol and diethyl ether and dissolved in dilute aqueous sodium hydroxide solution. The solution is washed with diethyl ether and adjusted to pH 8.5 with ammonium chloride. The precipitate formed is isolated, washed with methanol and then with diethyl ether and dried. In this way 2- (p-hydroxyphenyl) -

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24 pyrazolo [4,3-c] quinolin-3 (5H) -one, melting at 294-296 ° C.

Example 13

A solution of 1.9 g of 2- (p-nitrophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one is hydrogenated in a mixture of 18.6 ml of 2 N 5 aqueous sodium hydroxide solution and 75 ml. ethanol over 0.2 g of platinum oxide for 6 hours at a pressure of 2.7 atm. The mixture is filtered, the filtrate is evaporated, the residue is taken up in water and the solution is washed with diethyl ether. The solution is adjusted to pH 8.5 with ammonium chloride, the precipitated precipitate is isolated and washed with methanol and diethyl ether in the order in which it is dried. In this way, 2- (p-aminophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, whose IR spectrum has bands at 896, 885, 865, 840, 820, 815, 782, is prepared. 776, 761, 740, 736 and 720 cm "1.

Example 14.

To a mixture of 2- (p-aminophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, 1.4 g of 37% aqueous formaldehyde, 1 g of sodium cyanoborohydride and 20 ml Acetonitrile is added with stirring 0.6 g of glacial acetic acid. The mixture is stirred at room temperature overnight, then diluted with water. The precipitate formed is dissolved in dilute sodium hydroxide solution, the aqueous solution is washed with diethyl ether and adjusted to pH 8.5 with aqueous ammonium chloride solution. The precipitate formed is isolated, washed first with methanol and then with diethyl ether, then the precipitate is dried. In this way 2- (p-methyl-aminophenyl) -pyrazolo [4,3-c] -quinolin-3 (5H) -one is prepared which melts at 302-304 ° C.

Example 15

A mixture of 0.7 g of 2- (p-aminophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, 1.4 g of methyl isocyanate and 25 ml of methanol is refluxed for 7 hours, then overnight at room temperature. The mixture is then evaporated and the residue is treated with dilute aqueous liquid

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sodium hydroxide solution and diethyl ether, the aqueous solution is isolated, washed with diethyl ether and adjusted to pH 8.5 with ammonium chloride. The resulting precipitate is isolated, washed first with methanol and then with diethyl ether and then dried. In this way, 2- (p-methylcarbamoylaminophenyl) -pyrazolo [4,3-c] guinolin-3 (5H) -one, whose IR spectrum has bands at 895, 869, 850, 825, 816, 812, 785, is prepared. 780, 767 and 738 cm "1.

Example 16.

A mixture of 38.5 ml of 0.17 molar solution of 4-chloro-quinoline-3-carboxylic acid ethyl ester in xylene and 0.96 g of p-cyanophenylhydrazine in 30 ml of xylene is stirred for 3 hours under heating to 115 ° C. 120 ° C. The mixture is cooled to room temperature and stirred with 20 ml of 1 N aqueous sodium hydroxide solution and a sufficient amount of water to dissolve the solid. The aqueous layer is isolated, washed twice with diethyl ether and then treated with an aqueous solution of 1.07 g of ammonium chloride. The resulting precipitate is isolated, washed with water and dried. In this way, 2- (p-cyanphenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, whose IR spectrum has bands at 885, 830, 780, 755 and 730 cm 1, is prepared.

Example 17

1 g of 2- (p-cyanophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, 3.50. 1 ml aqueous sodium hydroxide solution and 10 ml ethanol are mixed and stirred at room temperature to dissolve the solid. Then, the solution is treated with 1.4 ml of 30% hydrogen peroxide, which immediately precipitates a precipitate. The mixture is stirred for 2 hours at room temperature, filtered and the solid is recrystallized from dimethylformamide. In this way, 2- (p-carbamoylphenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, whose IR spectrum has bands at 885, 853, 830, 785, 775, 752 and 732 cm first

26

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Example 18.

1 g of 2- (p-cyanphenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one and 50 ml of 2N aqueous sodium hydroxide solution are mixed and cooled for 3 hours under reflux. The solution is acidified with 50 ml of hydrochloric acid, filtered and the separated precipitate is dried. This precipitate is taken up in 25 ml of 1 N aqueous sodium hydroxide solution and the solution is adjusted to pH 6-7 with 1 N hydrochloric acid. The solid formed formed is filtered off, triturated with water and dried. In this way, 2- (p-carboxyphenyl) -pyrazolo [4,3-c] quinoline-3 (5H) -one 3/2 hydrate is produced whose IR spectrum has bands at 886, 858, 820, 780 , 770, 760 and 730 cm "1.

Example 19.

A solution of 1 g of 4-chloro-quinoline-3- (N-phenyl-N-trifluoroacetamido) carboxamide in a minimum amount of 50% aqueous tetrahydrofuran is adjusted to pH 10 by the addition of lithium hydroxide. The mixture is stirred for 48 hours at room temperature, concentrated to remove most of the tetrahydrofuran, washed with dichloromethane and adjusted to pH 3 by acidification with dilute hydrochloric acid. The resulting precipitate is filtered off under suction and purified by preparative thin layer chromatography on silica gel. Elute with a mixture of toluene, ethanol and concentrated ammonium hydroxide in the 70: 30: 3 mixture ratio.

In this way, 2-phenyl-pyrazolo [4,3-c] quinolin-3 (5H) -one is prepared which melts at 326-328 ° C.

The starting material is prepared as follows: A solution of 10.8 g of phenylhydrazine in 120 ml of diethyl ether is cooled with ice and 10.5 g of trifluoroacetic anhydride in 25 ml of diethyl ether are added dropwise over 15 minutes.

The mixture is stirred at 0-5 ° C for 15 minutes and then at room temperature for 2 hours, after which it is filtered. The filtrate is washed with water, dried, evaporated and the residue recrystallized from a mixture of diethyl ether and n-heptane. In this way, β-trifluoroacetyl-phenylhydrazine is prepared as 27

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melting at 119-121 ° C.

A mixture of 1.5 g of the above-prepared compound, 100 ml of tetrahydrofuran and 0.06 g of lithium hydride is stirred for 5 hours at room temperature 5 to form a solution. Separately, 1.9 g of 4-chloro-3-chlorocarbonyl-quinoline hydrochloride in 100 ml of tetrahydrofuran is stirred with 0.06 g of lithium hydride for 1 minute at 10 ° C, and this solution is added in portions of 10 ml to it. solution prepared above. The reaction mixture is stirred for 18 hours at room temperature, then refluxed for 8 hours, then concentrated under reduced pressure. In this way, 4-chloro-quinoline-3- (N-phenyl-N-trifluoroacetamido) carboxamide is prepared, as described above, without further purification.

Example 20.

A mixture of 0.211 g of 4- (O-methylhydroxylamino) quinoline-3- (N-p-chlorophenyl) carboxamide and 15 ml of eutectic diphenyl ether biphenyl is heated in a nitrogen atmosphere for 2 hours to 240 ° C. The mixture is cooled to room temperature, diluted with 150 ml of petroleum ether and the resulting precipitate is isolated. The precipitate is washed with petroleum ether, stirred for 1 hour with 15 ml of diethyl ether and 3 ml of 2N aqueous sodium hydroxide solution, the solid is filtered off and the phases in the filtrate are separated. The aqueous phase is treated with 0.32 g of ammonium chloride. A yellow precipitate is formed which is isolated and recrystallized from ethanol. In this way 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, which melts at 327 ° C, is prepared. The product is identical to the product of Example 1.

The starting compound is prepared as follows: A mixture of 11.62 g of 4-hydroxy-quinoline-3-carboxylic acid [M.Hamana et al., Chem. Pharm. Bull., 26, 3856 (1978)], 7.84 g of p-chloro-aniline, 17.59 g of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and 150 ml of dimethylformamide are heated for 2 hours to 60 ° C. 70 ° C

28

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to form a clear solution. The solution is cooled, filtered and evaporated on a rotary evaporator. The residue is triturated in diethyl ether, filtered and the precipitate is washed with diethyl ether. A mixture is obtained which contains the remainder of the acid used as the starting material. The mixture is stirred with 100 ml of 2N aqueous sodium hydroxide solution for 1.5 hours, filtered, washed with water and dried. In this way, 4-hydroxyquinoline-3- (Np-chlorophenyl) carboxamide is prepared, whose IR spectrum exhibits bands at 3450, 3260 and 3210 cm @ -1. A mixture of 1 g of the above compound and 25 ml of phosphorus oxychloride is heated for 3 hours. to 80 ° C to form a clear solution. The solution is evaporated, the residue is treated with 400 ml of a 1: 1 mixture of ice and 2N aqueous sodium hydroxide solution, stirred with 200 ml of dichloromethane, filtered and the phases are separated. The organic phase is dried and evaporated. In this way, 4-chloro-quinoline-3- (N-p-chlorophenyl) carboxamide is obtained, which melts at 229-234 ° C. (This compound can also be prepared by first treating the acid with phosphorus oxychloride 20 and then the dichloride produced with the indicated aniline.)

A mixture of 0.5 g of the compound prepared above, 1 g of O-methylhydroxylamine hydrochloride and 1.65 g of diisopropylethylamine is heated in a small pressure vessel for 18 hours to 100 ° C. The cooled mixture is triturated with water, dissolved in tetrahydrofuran, dried, evaporated and the residue recrystallized from methanol. In this way, 4- (0-methylhydroxylamino) -quinoline-3- (N-p-chlorophenyl) carboxamide, which melts at 210-212 ° C, is prepared.

Example 21.

A solution of 308 mg of 1- (p-chlorophenyl) -4-hydroxymethylene-3- (o-nitrophenyl) -4,5-dihydropyrazol-5-one in 80 ml of tetrahydrofuran is hydrogenated over 50 mg of 5% platinum on carbon catalyst at room temperature and a pressure of 3 atm. for half an hour. The mixture is filtered, the filtrate is evaporated and the residue 29

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then taken up in 150 ml of toluene. To the solution is added 0.1 ml of concentrated hydrochloric acid and the mixture is boiled using a water separator for 18 hours at reflux. The mixture is cooled, the precipitate formed is filtered and purified by preparative thin layer chromatography on silica gel. As a solvent, a mixture of ethyl acetate, ethanol and concentrated ammonium hydroxide is used in the mixture ratio 17: 3: 3. In this way 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, which melts at 327 ° C, is prepared.

The product is identical to the product of Example 1.

The starting compound is prepared as follows: A solution of 39.6 g of malonic acid monoethyl ester, 50 mg of 2,2-bipyridyl (indicator) and 650 ml of tetrahydrofuran is cooled to -70 ° C, and 305 ml is slowly added with stirring in a nitrogen atmosphere. 1.97 M n-butyllithium in hexane. Towards the end of the addition, after the indicator's pink-red color does not disappear, allow the temperature to rise to approx. -5 ° C. The mixture is again cooled to -65 ° C and a solution of 31.7 20 g of o-nitrobenzoyl chloride in 50 ml of tetrahydrofuran is added dropwise over 10 minutes. The resulting mixture is stirred for 1 hour at room temperature, then poured into a mixture of 650 ml of 1 N hydrochloric acid and 1100 ml of diethyl ether. The organic layer is isolated, washed with 350 ml of saturated aqueous sodium bicarbonate solution, 400 ml of water and 200 ml of saturated aqueous sodium chloride solution in the order in which it is dried and evaporated. In this way 2- (o-nitrobenzoyl) -acetic acid ethyl ester is prepared in the form of a colorless oil.

A solution of 3.55 g of the above compound and 1.7 g of p-chlorophenylhydrazine in 65 ml of toluene is boiled using water separator for 3 hours under reflux. The mixture is evaporated and the residue is chromatographed on silica gel and heated with 15% ethyl acetate in toluene. In this way, 1- (p-chlorophenyl) -3-30 is prepared

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(o-nitrophenyl) -4,5-dihydro-pyrazol-5-one, which melts, at 138-141 ° C.

0.7 g of the above compound is stirred in 10 ml of a mixture of dimethylformamide and dimethyl acetal 5 at room temperature for 18 hours. The dark reaction mixture is poured into ice water, the precipitate is filtered off with suction, taken up in ethyl acetate, then washed with water, dried and evaporated. In this way, 1- (p-chlorophenyl) -4-dimethylaminomethylene-3-one-nitrophenyl-4,5-dihydropyrazol-5-one is prepared which melts at 208-210 ° C with decomposition.

2.5 g of the above compound is stirred in a mixture of 20 ml of tetrahydrofuran and 20 ml of 20% aqueous hydrochloric acid first at 60 ° C for 3 hours and then at room temperature for 18 hours. The mixture is diluted with saturated aqueous sodium chloride solution, the precipitate is isolated and washed with ethyl acetate. In this way, 1- (p-chlorophenyl) -4-hydroxymethylene-3- (o-nitrophenyl) -4,5-dihydropyrazol-5-one is prepared which melts at 155-157 ° C.

Example 22.

A mixture of 650 mg of 1- (p-chlorophenyl) -2-methyl-4-anilino-methylidene-pyrazolidine-3,5-dione, 2 g of polyphosphoric acid ethyl ester and 10 ml of 1,1,2,2-tetrachloroethane is boiled. for 24 hours at reflux. The solution is poured into 10 ml of 2N aqueous sodium hydroxide solution and the organic layer is chromatographed on silica gel plates and eluted with a mixture of toluene, ethanol and concentrated ammonium hydroxide in the 80: 20: 1 mixture ratio. In this way, 1-methyl-2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3-one is prepared with an Rf value of 0.48. When a mixture of dichloromethane 30 and methanol in the 19: 1 mixture ratio is used as the eluent, said compound has an Rf of 0.33. The product is identical to the product of Example 4.

The starting material is prepared as follows: 20 mg malone-31

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acid diethyl ester is added to 5.8 g of sodium metal which is dissolved in 100 ml of absolute methanol. The mixture is stirred for 15 minutes, then 17.8 g of p-chlorophenylhydrazine is added and excess ethanol is removed with suction. The residue is heated at 110-120 ° C for 4.5 hours, then quenched with 500 ml of ice water. The resulting mixture is washed twice with diethyl ether and the aqueous phase adjusted to pH 2 with concentrated hydrochloric acid. The solid formed is recrystallized from toluene. In this way, 1- (p-10-chlorophenyl) -pyrazolidine-3,5-dione is prepared which melts at 189-193 ° C.

A mixture of 2 g of the compound prepared above, 2.81 g of orthoic acid triethyl ester, 0.97 g of aniline and 30 ml of ethanol is refluxed for 16 hours. The reaction mixture is cooled, filtered and the precipitate is washed with 15 water. In this way, 1- (p-chlorophenyl) -4-anilinomethylidene-pyrazolidin-3,5-one is prepared which melts at 288-290 ° C.

A mixture of 500 mg of the compound prepared above, 15 mg of lithium hydride and 2 ml of dimethylformamide is heated to 70 ° C for three hours. The solution is then cooled to 5 ° C and 700 mg of methyl iodide is added. The mixture is stirred for 16 hours at room temperature and then evaporated. The residue is taken up in a mixture of water and dichloromethane, the organic phase is isolated, dried and evaporated. In this way, 1- (p-chlorophenyl) -2-methyl-4-anilinomethylidene-pyrazolidin-3,5-dione, whose NMR spectrum exhibits bands at 3.14, 7.47, 8.42, 10, is prepared. 92 and 10.98 ppm.

Example 23

A solution of 50 mg of 1- (p-chlorophenyl) -3- (o-formylamino-phenyl) -4,5-dihydropyrazol-5-one in 10 ml of dichloromethane is evaporated leaving a thin film on the inner wall of the flask. . This is heated for 30 minutes in a slow nitrogen stream to 190-200 ° C. The reaction product is chromatographed on silica gel plates and eluted with a mixture of ethyl acetate.

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acetate, ethanol and concentrated ammonium hydroxide in the 17: 3: 3 mixture ratio. In this way 2- (p-chloro-phenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one, having an Rf value of 0.16, is prepared. When 5% methanol is used, in dichloro-5 methane, the compound has an Rf of 0.07. With a mixture of toluene, ethanol and concentrated ammonium hydroxide in the mixture ratio of 70: 30: 3, the Rf value is 0.32.

The starting material is prepared as follows: In 100 ml of ethanol, 2 g of 1- (p-chlorophenyl) -3- (o-nitrophenyl) -10 4,5-dihydropyrazol-5-one over 200 mg of 5% paltin-on-hydrogen are hydrogenated. carbon catalyst at room temperature and a pressure of 3 atm. As the product is separated from the reaction mixture immediately after its formation, the reaction mixture is diluted with dichloromethane to dissolve the crystalline product. The mixture is filtered, the filtrate is evaporated and the dried residue is recrystallized from ethanol. In this way, 3- (o-aminophenyl) -1- (p-chlorophenyl) -4,5-dihydropyrazol-5-one is prepared which melts at 199-201 ° C.

0.3 g of the above compound is added in a 20 nitrogen atmosphere under ice-cooling and stirring to 10 ml of 97% Ts formic acid to form a colorless solution.

To this solution is added 1 ml of acetic anhydride, then stirred overnight at room temperature, and the mixture is poured into 300 ml of saturated aqueous sodium chloride solution. The colorless precipitate is isolated, dissolved in 200 ml of diethyl ether, dried and evaporated. In this way, 1- (p-chlorophenyl) -3- (o.-formylaminophenyl) -4,5-dihydropyrazol-5-one is prepared which melts at 170-172 ° C.

Example 24.

Analogous to the above examples, especially in the process illustrated in Examples 1 and 8-11, the following compounds of formula II are also prepared in which R

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No. R_ R Mp. in ° C or IR band J. 1-cm-1 8-CH 3 O-2-pyridyl 319 - 323 2 7-CF 3 -2-pyridyl 348 - 350 53 H 4-CH 3 ~ 2-pyridyl 342 - 344 4 H 5-Cl-2-pyridyl 886,835,828,797,778,756 5 H 2,5-Cl 2 -phenyl 337 - 338 6 H 3,4-Cl 2 -phenyl 890,878,867,823,818,795 7 H 3,5-Cl2-phenyl 890,871,847,830,806,788 The following compounds of formula III are prepared by analogy to the procedures illustrated in the above examples:

No. R "R 'mp i ° C or IR bands in -1 cm 8 H O_CH3 349" 350 (HCl salt) 15 9 HP "CH3 338" 340 10 H p-OCH3 268 - 270 11 p-SCH3 307 - 309 12 H pF 342 - 346 13 H mF 335 - 338 20 14 H oF 338 - 340 15 H o-Cl 336 - 339 16 H m-Cl 336 - 337 17 H p-Br 328 - 330 18 HP "CF3 315 320 320 19 H-p-NO2 886,853,818,780,758,749 20 7-C1 H 872,851,830,818,798,770 21 7-Cl p-Cl 865,852,823,795,768,752 22 7-Cl pF 890,858,835,804,770,731 23 7-Cl m-Cl 333 - 335 8.78.78.78.78.78.78.78.78.78.78.78.77 p-CH3 340 - 342 26 8 “CH3 pC! 335 - 337 34

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Continued 27 8-OCH3 H 321 - 325 28 8-OCH3 p-OCH3 313 - 315 29 8-OCH3 or 344 - 347 5 30 8-OCH3 m-Cl 324 - 327 31 8-OCH3 p-Cl 347 - 349 32 8 -FH 327 - 328 33 8-F p-OCH3 289 - 292 34 8-F pF 884,868,827,767,715,708 10 35 8-F mF 900,881,865,839,827,774 36 8-F oF 868,850,815,782,750,724 37 8-F p-Cl 342 - 345 38 8-F m- Cl 870,810,800,775,760,714 39 8-C1 H 894,871,845,812,787,770 115 40 8-Cl oF 895,875,858,820,814,782 41 8-Cl mF 892,884,867,860,815,771 42 8-Cl pF 898,890,870,855,832,820 43 8-Cl o-Cl 896,885,8 Cl 890,865,815,790,777,740 46 8-Cl p-N02 895,882,849,834,808,784 47 8-F p-N02 896,884,869,860,828,821 48 8-OCH3 p-N02 338 - 340 49 6-C1 p-Cl 825,806,762,736,720 25 50 7_CF3 331 "334 52 7" CF3 'm-Cl 317 - 320 53 7 ~ cf3 pC! 890,854,826,800,770,756 35

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Example 25

Analogous to the procedure described in Example 4, the following compounds of formula I are also prepared: 5 a) 1-Ethyl-2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3-one, sp. 174-177 ° C.

b) 1-methyl-2-phenyl-pyrazolo [4,3-c] quinolin-3-one, m.p. 204-207 ° C.

c) 2- (p-Methoxyphenyl) -1-methyl-pyrazolo [4,3-c] quinolin-3-one, m.p. 159-162 ° C.

Claims (3)

1. Analogous Process for the Preparation of 2-phenyl or 2-pyridyl-pyrazolo [4,3-c] quinoline-3 (1 and 5H) -5one Compounds of the General Formulas% II% II in hCi wherein R 1 represents hydrogen, lower alkoxy, halogen or trifluoromethyl, R means unsubstituted or having at most 2 identical or different substituents selected from lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono - or di-lower alkylamino, cyano, carbamoyl and lower alkylcarbamoylamino substituted phenyl, pyridyl, lower alkylpyridyl or halogenpyridyl, R 1 represents hydrogen, lower alkyl or di-lower alkyl amino lower alkyl, and R 1-4 carbon atoms, the 3-hydroxytautomers, or their salts, characterized in that compounds of the formula X X \ s sCO s, T „s% -rs are terminated; α)> W wherein X is -NH-NH-R, where R and R3 have the meanings given above and Y is hydroxy or lower alkoxy, compounds containing formula IV wherein X is halogen and Y is H2N No. 5 wherein R and R3 have the above meanings, or lc) ring ends compounds of formula IV wherein X is lower alkoxyamino and Y is -NH-R and R and R3 have the above meanings, or 2a) condenses compounds of the formula R 1'-f-jjr-R (/ ν '% (Va)% \ II 10 ΐ 5 / -¾ vv H wherein R 1 is lower alkyl and R, R 2 and R 3 have the above meanings, condensates compounds of formula R r |R (Vb) 3> / / / é I I R R NH NHHH wherein R, R₂ and R3 have the meanings given above, 2c) condenses compounds of formula DK 160762 B 1 in which R, R 2 and R 3 have the meanings given above, and a) when a compound in which R 1 at 1 position 5 is different from hydrogen is desired, is a resultant compound wherein R 1 is hydrogen with a reactive ester of an alcohol R 1'-OH, wherein r 1 is the one given above for R 1 other than hydrogen, (b) when a compound wherein R 1 the position 10 is different from hydrogen, reacting an alkali metal salt of a resultant compound wherein R 1 is hydrogen, with a reactive ester of an alcohol r '{' -OH wherein RJ 'has the meaning given above for R 1 other than hydrogen, c) when a compound in which the phenyl group R is substituted by hydroxy is desired, hydrolyzes a lower alkoxy substituent on the phenyl group R, d) when a compound in which the phenyl group R is substituted with amino is reduced, a nitro substituent on the phenyl group R, 20 e) when a compound in which the phenyl group R is substituted by mono- or di-lower alkylamino is desired, the amino substituent on the phenyl group R, f) when a compound in which the phenyl group R is substituted with laval is desired (g) when desired a compound wherein the phenyl group R is substituted by carbamoyl converts a cyano substituent of the phenyl group R to carbamoyl and then h) if desired, a resulting compound converts to its salt or an resulting salt to the free compound or to another salt, and / or i) if desired, a resulting isomeric mixture separates into the 10 individual isomers. Process according to claim 1, characterized in that 2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one or salts thereof are prepared. Process according to claim 1, characterized in that 2-phenyl-pyrazolo [4,3-c] quinolin-3 (5H) -one or its salts are prepared.